The present invention is directed to novel 2-aminopyridine compounds, their salts, and compositions comprising them. In particular, the present invention is directed to novel 2-aminopyridine compounds that inhibit the activity of tyrosine kinase enzymes in animals, including humans, for the treatment and/or prevention of various diseases and conditions such as cancer.
Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of specific tyrosine residues in various cellular proteins involved in regulation of cell proliferation, activation, or differentiation (Schlessinger and Ullrich, 1992, Neuron 9:383-391). Aberrant, excessive, or uncontrolled PTK activity has been shown to result in uncontrolled cell growth and has been observed in diseases such as benign and malignant proliferative disorders, as well as having been observed in diseases resulting from an inappropriate activation of the immune system (e.g., autoimmune disorders), allograft rejection, and graft vs. host disease. In addition, endothelial-cell specific receptor PTKs such as KDR and Tie-2 mediate the angiogenic process, and are thus involved in supporting the progression of cancers and other diseases involving inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, infantile hemangiomas). Other kinases that are believed to be important mediators of tumor angiogenesis include FGFR3, Tie-2, and Flt3. For example, FGFR3 mutations are often seen in bladder cancer cells. Tie-2 is a protein receptor found on cells lining blood vessels. When activated by growth factors secreted by tumor cells, Tie2 triggers vessel cell walls to part and grow new capillaries. Flt3, also known as “vascular endothelial cell growth factor receptor 3” or VEGFR-3, is believed to assist in vascular development important to angiogenesis. Thus, it is desirable to identify inhibitors of FGFR3, Tie-2, and/or Flt3.
Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular). The Receptor Tyrosine Kinases (RTKs) comprise a large family of transmembrane receptors with at least nineteen distinct RTK subfamilies having diverse biological activities. The RTK family includes receptors that are crucial for the growth and differentiation of a variety of cell types (Yarden and Ullrich, Ann. Rev. Biochem. 57:433-478, 1988; Ullrich and Schlessinger, Cell 61:243-254, 1990). The intrinsic function of RTKs is activated upon ligand binding, which results in phosphorylation of the receptor and multiple cellular substrates, and subsequently results in a variety of cellular responses (Ullrich & Schlessinger, Cell 61:203-212, 1990). Thus, RTK mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of the intrinsic protein tyrosine kinase activity and receptor trans-phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate a corresponding cellular response such as cell division, differentiation, metabolic effects, and changes in the extracellular microenvironment (Schlessinger and Ullrich, Neuron 9:1-20, 1992).
In appropriately high protein kinase activity has been implicated in many diseases resulting from abnormal cellular function. This might arise either directly or indirectly by a failure of the proper control mechanisms for the kinase, related to mutation, over-expression or inappropriate activation of the enzyme; or by an over- or underproduction of cytokines or growth factors participating in the transduction of signals upstream or downstream of the kinase. In all of these instances, selective inhibition of the action of the kinase might be expected to have a beneficial effect.
Many of the tyrosine kinases, whether an RTK or non-receptor tyrosine kinase, have been found to be involved in cellular signaling pathways involved in numerous disorders, including cancer, psoriasis, fibrosis, atherosclerosis, restenosis, auto-immune disease, allergy, asthma, transplantation rejection, inflammation, thrombosis, nervous system diseases, and other hyperproliferative disorders or hyper-immune responses. It is desirable to provide novel inhibitors of kinases involved in mediating or maintaining disease states to treat such diseases.
Cells may migrate and divide inappropriately if the signals for division or motility cannot be stopped. This might occur if the complex system of control proteins and messengers, which signal changes in the actin system, goes awry. One such control factor is the proto-oncogene protein Ab1, a tyrosine kinase. It is implicated in cancer, including leukemia. Accordingly, it is desirable to identify inhibitors of Ab1.
The Aurora kinase family is one regulator of chromosome segregation—regulating the structure and function of centrosomes and mitotic spindle. One member, the Aurora-A kinase, has been shown to play a role in tumorigenesis—being located at a chromosomal hot-spot, 20q13, frequently amplified in a variety of human cancers such as those of colon, ovary, breast and pancreas. It appears that overexpression of Aurora-A kinase alone is sufficient to cause aneupoidy in normal diploid epithelial cells. Over-expression of Aurora-A kinase in NIH3T3 cells results in centrosome aneupoidy. Thus, it is desirable to identify inhibitors of Aurora-A.
The cytoplasmic tyrosine kinase c-Src is involved in the signal transduction pathway and is elevated in breast cancer cell lines. Similarly, Src is involved in the regulation of cell growth and transformation. Thus over-expression of c-Src can lead to excess proliferation. Thus, it is desirable to identify inhibitors of c-Src.
IGF-1R (type 1 insulin-like growth factor receptor) performs important roles in cell division, development, and metabolism, and in its activated state, plays a role in oncogenesis and suppression of apoptosis. IGF-1R is known to be overexpressed in a number of cancer cell lines (IGF-1R overexpression is linked to acromegaly and to cancer of the prostate). By contrast, down-regulation of IGF-1R expression has been shown to result in the inhibition of tumorigenesis and an increased apoptosis of tumor cells. Thus, it is desirable to identify compounds that inhibit IGF-1R.
ALK (Anaplastic Lymphoma Kinase) is a receptor tyrosine kinase that belongs to the insulin receptor subfamily. It is implicated in the progression of certain tumors such as anaplastic large cell lymphomas (ALCL; Kutok J. L. & Aster J. C., J. Clin Oncol., 20:3691-3702, 2002; Duyster J. et al., Oncogene, 20:5623-5637, 2001), inflammatory myofibroblastic tumors (IMT; Duyster J. et al.), and glioblastomas (Powers C. et al, J. Biol Chem., 276:16772-16779, 2001). It has been demonstrated that inhibition of ALK can impair the growth and induce apoptosis of lymphoma cells containing ALK (Turturro F. et al., Clin. Cancer Res., 8:240-245, 2002). Thus, it is desirable to identify compounds that inhibit ALK.
RON (recepteur d′ origine nantais) is a receptor tyrosine kinase that is part of the MET proto-oncogene family. It is activated by binding to its natural ligand MSP and signals via the PI3K and MAPK pathways. RON can be deregulated in cancer by mechanisms such as over-expression of the receptor and/or the presence of constitutively active splice variants. Inhibition of RON has been shown to lead to a decrease in proliferation, induction of apoptosis and affects cell metastasis. RON overexpression is observed in a variety of human cancers and exhibit increased expression with progression of the disease.
MET is a receptor tyrosine kinase that is a heterodimeric protein comprising of a 50 kDa α-subunit and a 145kDa β-subunit (Maggiora et al, J. Cell Physiol, 173:183-186, 1997). It is activated by binding to its natural ligand HGF (hepatocyte growth factor, also known as scatter factor) and signals via the PI3K and MAPK pathways. MET can be deregulated in cancer by mechanisms such as autocrine/paracrine HGF activation, over-expression of the receptor, and/or the presence of activating mutations. Significant expression of MET has been observed in a variety of human tumors, such as colon, lung, prostate (including bone metastases), gastric, renal, HCC, ovarian, breast, ESCC, and melanoma (Maulik et al, Cytokine & Growth Factor Reviews 13:41-59, 2002). MET is also implicated in atherosclerosis and lung fibrosis. Inhibition of MET can cause a decrease in cell motility, proliferation and metastasis, as reviewed in, e.g., Chemical & Engineering News 2007, 85 (34), 15-23.
As human cancers progress to a more invasive, metastatic state, multiple signaling programs regulating cell survival and migration programs are observed depending on cell and tissue contexts (Gupta and Massague, 2006). Recent data highlight the transdifferentiation of epithelial cancer cells to a more mesenchymal-like state, a process resembling epithelial-mesenchymal transition (EMT; (Oft et al., 1996; Perl et al., 1998), to facilitate cell invasion and metastasis (Brabletz et al., 2005; Christofori, 2006). Through EMT-like transitions mesenchymal-like tumor cells are thought to gain migratory capacity at the expense of proliferative potential. A mesenchymal-epithelial transition (MET) has been postulated to regenerate a more proliferative state and allow macrometastases resembling the primary tumor to form at distant sites (Thiery, 2002). MET and RON kinases have been shown to play a role in the EMT process (Camp et al., 2007; Grotegut et al., 2006; Wang et al., 2004).
Thus, it is desirable to identify inhibitors of RON and/or it related family MET for use in proliferative diseases, such as, but not limited to, cancer.
It has been documented in vitro that RON and MET can form heterodimers and signal via such RON-MET dimers. Since co-expression of RON and MET in cancer has been observed, such “cross-talk” may contribute to tumor growth. It is therefore especially desirable to identify compounds that inhibit both RON and MET.
In view of the importance of PTKs to the control, regulation, and modulation of cell proliferation and the diseases and disorders associated with abnormal cell proliferation, many attempts have been made to identify small molecule tyrosine kinase inhibitors. International Patent Publications Nos. WO 2006/021881 and WO 2004/076412 describe 3-alkoxysubstituted 2-aminopyridines and 2-aminopyrazines as kinases inhibitors. International Patent Publication No. WO 2004/069160 describes benzimidazolyl-pyridines as SGK-1 inhibitors. International Patent Publication No. WO 2007/111904 describes tetrazolyl substituted pyridinamines or pyrazinamines as c-Met protein kinase inhibitors.
Although the anticancer compounds described above have made contribution to the art, there is a continuing need to improve anticancer pharmaceuticals with better selectivity or potency, reduced toxicity, or fewer side effects.
It has been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of kinases. In particular, the compounds are effective as inhibitors of at least one of the KDR, Tie-2, Flt3, FGFR3, Ab1, Aurora A, c-Src, IGF-1R, ALK, c-MET, RON, PAK1, PAK2, and TAK1 kinases.